Many patients with B cell malignancies are incurable with standard therapy. In addition, traditional treatment options often have serious side effects. Attempts have been made in cancer immunotherapy, however, several obstacles render the goal of clinical effectiveness difficult to achieve. Although hundreds of so-called tumor antigens have been identified, these are generally derived from self and thus are poorly immunogenic. Furthermore, tumors use several mechanisms to render themselves hostile to the initiation and propagation of immune attack.
Recent developments using chimeric antigen receptor (CAR) modified autologous T cell (CART) therapy, which relies on redirecting T cells to a suitable cell-surface molecule on cancer cells such as B cell malignancies, show promising results in harnessing the power of the immune system to treat B cell malignancies and other cancers (see, e.g., Sadelain et al., CANCER DISCOVERY 3:388-398 (2013)). For example, the clinical results of a CART that binds to CD19 (i.e., “CTL019”) have shown promise in establishing complete remissions in patients suffering with chronic lymphocytic leukemia (CLL), as well as in childhood acute lymphocytic leukemia (ALL) (see, e.g., Kalos et al., SCI TRANSL MED 3:95ra73 (2011), Porter et al., NEJM 365:725-733 (2011), Grupp et al., NEJM 368:1509-1518 (2013)).
Besides the ability for the chimeric antigen receptor on the genetically modified T cells to recognize and destroy the targeted cells, a successful therapeutic T cell therapy needs to have the ability to proliferate, to persist over time, and to further monitor for leukemic cell escapees. The variable phenotypic state of T cells, whether it is in a state of anergy, suppression or exhaustion, will have effects on CAR-transformed T cells' efficacy. To be effective, CAR transformed patient T cells need to persist and maintain the ability to proliferate in response to the CAR's antigen.
A need, therefore, exists for a method of using biomarkers for use in connection with the differential diagnosis and treatment of cancer with CAR-expressing cell (e.g., T cell, NK cell) therapy. In particular, there is an unmet need for effective predictors of therapeutic response in subjects having a hematological cancer, such as CLL and ALL, to a CAR-expressing cell therapy, e.g., with CTL019 or other CD19 CAR-expressing cells.